The present invention relates to a process for producing a tetrahydropyranyl-4-sulfonate and a process for producing a 4-aminotetrahydropyran compound from the tetrahydropyranyl-4-sulfonate. The tetrahydropyranyl-4-sulfonate is a useful compound for introducing a tetrahydropyranyl group into various compounds by substitution of a sulfonyl group, and the 4-aminotetrahydropyran compound is a useful compound as a synthetic intermediate or a starting material for medicines, agricultural chemicals, and the like.
As a process for producing a tetrahydropyranyl-4-sulfonate from 3-buten-1-ol, there has been known a process for producing it by two steps through a tetra-hydropyran-4-ol, for example, 3-buten-1-ol and formalin are reacted in the presence of sulfuric acid to synthesize the tetrahydropyran-4-ol with a yield of 76% (Chem. Ber., 88, p.1053 (1955)), and then, in the presence of a base, the tetrahydropyran-4-ol and methanesulfonyl chloride are reacted to synthesize a tetrahydropyranyl-4-methanesulfonate with an yield of 35% (J. Chem. Soc., 1952, p.910), and the like.
Also, as a process for producing a 4-aminotetrahydropyran compound, there have been known, for example, a method of contacting an ammonia gas and a hydrogen gas with a tetrahydropyran-4-one in the presence of Raney Nickel (Helv. Chim. Acta, 47, 2145 (1964)), a method of reacting a tetrahydropyran-4-one and an amine in the presence of sodium cyanoborohydride (J. Med. Chem., 37, 565 (1994)), a method of heating a tetrahydropyran-4-one in a mixed solution of water, N,N-dimethylformamide and formic acid (Japanese Provisional Patent Publication No. Hei.11-263764) and the like. However, the tetrahydropyran-4-one is a compound synthesis of which is relatively difficult and is a compound extremely unstable to a base and troublesome in handling since it is ring-opened easily and forms polymers, and there is a problem that an yield of the objective 4-aminotetrahydropyrane compound is low in either of the methods.
On the other hand, there is disclosed a method in which a 4-chlorotetrahydropyrane and ammonia in an autoclave at 200xc2x0 C. (J. Org. Chem., 36, 522 (1971)), but the reaction conditions thereof are extremely strict and there is a problem of low yield.
An object of the present invention is to provide a process for producing a tetrahydropyranyl-4-sulfonate, which is industrially advantageous, from an easily available 3-buten-1-ol without requiring any complicated operations, with a simple and easy method and which is capable of producing the tetrahydropyranyl-4-sulfonate with one step and high yield.
Also, another object of the present invention is to provide a process for producing a 4-aminotetrahydropyrane compound which is industrially suitable, under mild conditions and by a simple and easy method to produce the 4-aminotetrahydropyrane compound in high yield.
The present invention relates to a process for producing a tetrahydropyranyl-4-sulfonate which comprises allowing 3-buten-1-ol to react with a formaldehyde derivative and an organic sulfonic acid.
Also, the present invention relates to a process for producing a 4-aminotetrahydropyran compound represented by the following formula (2): 
wherein R1 and R2 each represent a group which does not participate in the reaction; and R1 and R2 may form a ring by bonding to each other, which comprises allowing a tetrahydropyranyl-4-sulfonate to react with an amine represented by the following formula (1): 
wherein R1 and R2 have the same meanings as defined above.
First, a process for producing the tetrahydropyranyl-4-sulfonate of the present invention will be explained.
3-Buten-1-ol to be used as a starting material in the reaction of the present invention is a compound capable of being easily synthesized by dehydration reaction of 1,4-butanediol (for example, Bull. Chem. Soc. Jpn., 54, 1585 (1981)) or a monoepoxidation reaction of butadiene and a subsequent reduction (for example, WO 9936379).
As the formaldehyde derivative to be used in the reaction of the present invention, there may be mentioned an aqueous solution of formaldehyde or a polymer of formaldehyde, and, for example, formalin, paraformaldehyde and trioxane are suitably used.
An amount of the above-mentioned formaldehyde derivative is preferably 1.0 to 5.0-fold moles, more preferably 1.1 to 2.0-fold moles based on the starting material, 3-buten-1-ol (in terms of formaldehyde). These formaldehyde derivatives may be used singly or in combination of two or more.
As the organic sulfonic acid to be used in the reaction of the present invention, there may be mentioned, for example, an alkylsulfonic acid such as methanesulfonic acid, ethanesulfonic acid, etc.; an arylsulfonic acid such as benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, p-bromobenzenesulfonic acid, etc.
An amount of the above-mentioned organic sulfonic acid to be used is preferably 1.0 to 5.0-fold moles, more preferably 1.1 to 3.0-fold moles based on the starting material, 3-buten-1-ol.
The reaction of the present invention is carried out in the presence or absence of a solvent. As the solvent to be used, there may be mentioned, for example, water; an aromatic hydrocarbon such as benzene, toluene, xylene, mesitylene, etc.; a halogenated hydrocarbon such as chloroform, dichloroethane, etc.; an organic acid ester such as ethyl acetate, butyl acetate, etc.; an ether such as tetrahydropyrane, diisopropyl ether, etc., and preferably an aromatic hydrocarbon, more preferably, benzene, toluene, and particularly preferably toluene.
An amount of the above-mentioned solvent is preferably 0 to 50 ml, more preferably 0 to 10 ml based on 1 g of 3-buten-1-ol. These solvents may be used singly or in combination of two or more.
The reaction of the present invention is preferably carried out by contacting the starting materials, 3-buten-1-ol, the formaldehyde derivative and the organic sulfonic acid in a liquid phase, and may be carried out by a method in which, for example, under an inert gas atmosphere, 3-buten-1-ol, the formaldehyde derivative and the organic sulfonic acid are mixed and stirred under heating, and the like, under a normal pressure or under a pressure. An order of mixing the above-mentioned compounds is optional, and all are mixed simultaneously, or to either one or a mixture of two kinds, the remaining materials are optionally added stepwisely or simultaneously. A reaction temperature at the time is preferably 10 to 80xc2x0 C., more preferably 20 to 60xc2x0 C.
Incidentally, the tetrahydropyranyl-4-sulfonate which is a final product of the above-mentioned reaction can be, for example, purified by a general method such as distillation, recrystallization, column chromatography and the like, after removing the solvent after completion of the reaction.
Next, a process for producing a 4-aminotetrahydropyran compound of the present invention is explained.
The tetrahydropyranyl-4-sulfonate which is used as a starting material for the reaction of the present invention is a compound easily synthesized by allowing 3-buten-1-ol to react with the formaldehyde derivative (for example, formalin) and the organic sulfonic acid as described above.
As the above-mentioned tetrahydropyranyl-4-sulfonate, there may be mentioned, for example, tetrahydropyranyl-4-alkylsulfonate such as tetrahydropyranyl-4-methanesulfonate, tetrahydropyranyl-4-ethanesulfonate, etc.; tetrahydropyranyl-4-arylsulfonate such as tetrahydropyranyl-4-benzenesulfonate, tetrahydropyranyl-4-p-toluenesulfonate, tetrahydropyranyl-4-p-chlorobenzenesulfonate, tetrahydropyranyl-4-p-bromobenzenesulfonate, etc.
The amine to be used in the reaction of the present invention is represented by the above-mentioned formula (1). In the formula (1), R1 and R2 are groups which do not participate in the reaction, and more specifically, they may be the same or different from each other, and represents a hydrogen atom, an alkyl group, a cycloalkyl group, an aralkyl group or an aryl group, each of which may have a substituent(s). Also, R1 and R2 may form a ring by bonding to each other.
As the above-mentioned alkyl group, an alkyl group having 1 to 10 carbon atoms is particularly preferred, and, for example, there may be mentioned a methyl group, an ethyl group, a propyl group (and its isomer), a butyl group (and its isomers), a pentyl group (and its isomers), a hexyl group (and its isomers), a heptyl group (and its isomers), an octyl group (and its isomers), a nonyl group (and its isomers) and a decyl group (and its isomers).
As the above-mentioned cycloalkyl group, a cycloalkyl group having 3 to 7 carbon atoms is particularly preferred, and there may be mentioned, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.
As the above-mentioned aralkyl group, an aralkyl group having 7 to 10 carbon atoms is particularly preferred, and there may be mentioned, for example, a benzyl group, a phenethyl group (and its isomers), a phenylpropyl group (and its isomers) and a phenylbutyl group (and its isomers).
As the above-mentioned aryl group, an aryl group having 6 to 14 carbon atoms is particularly preferred, and there may be mentioned, for example, a phenyl group, a p-tolyl group, a naphthyl group and an anthranyl group.
The above-mentioned alkyl group, cycloalkyl group, aralkyl group or aryl group may have a substituent(s). As the substituent(s), there may be mentioned at least one selected from a substituent formed through a carbon atom, a substituent formed through an oxygen atom, a substituent formed through a nitrogen atom, and a halogen atom.
As the above-mentioned substituent formed through a carbon atom, there may be mentioned, for example, an alkyl group such as a methyl group, an ethyl group, a propyl group, etc.; an aralkyl group such as a benzyl group, etc.; an aryl group such as a phenyl group, etc.; and a cyano group.
As the above-mentioned substituent formed through an oxygen atom, there may be mentioned, for example, an alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a benzyloxy group, etc.; an aryloxy group such as a phenoxy group, etc.; an acyloxy group such as an acetoxy group, a benzoyloxy group, etc.
As the above-mentioned substituent formed through a nitrogen atom, there may be mentioned, for example, a nitro group; and an amino group.
As the above-mentioned halogen atom, there may be mentioned a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
As the amine to be used in the reaction of the present invention, an amine itself may be used, and in the case of an amine having a low boiling point at atmospheric pressure, it is preferably used as an aqueous solution or an alcoholic solution, which is easy to handle. A concentration thereof is preferably 1 to 90% by weight, more preferably 3 to 60% by weight.
An amount of the above-mentioned amine is preferably 1 to 60-fold moles, more preferably 3 to 40-fold moles based on an amount of the starting material, tetrahydropyranyl-4-sulfonate.
The reaction of the present invention is carried out in the presence or absence of a solvent. As the solvent to be used, there may be mentioned, for example, water; an amide such as N,N-dimethylformamide, etc.; an urea such as N,N-dimethylimidazolidinone, etc.; an alcohol such as methanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc.; an aromatic hydrocarbon such as benzene, toluene, xylene, mesitylene, etc.; a halogenated hydrocarbon such as methylene chloride, chloroform, dichloroethane, etc.; and preferably water and an alcohol, more preferably water, methanol and ethanol.
An amount of the above-mentioned solvent is preferably 0 to 50-fold weight, more preferably 0 to 20-fold weight based on the starting material, tetrahydropyranyl-4-sulfonate. These solvents may be used singly or in combination of two or more.
The reaction of the present invention is preferably carried out by contacting a tetrahydropyranyl-4-sulfonate and an amine in a liquid phase, for example, it is carried out by a method in which a tetrahydropyranyl-4-sulfonate and an amine are mixed under an inert gas atmosphere, and stirred under heating and the like, under atmospheric pressure or under pressure. A reaction temperature at that time is preferably 40 to 180xc2x0 C., more preferably 50 to 130xc2x0 C.
Also, if necessary, by adding an inorganic base or an organic base in the system, reactivity may be controlled.
Incidentally, the final product, the 4-aminotetrahydropyrane derivative is, for example, separated and purified after completion of the reaction by a conventional method such as distillation, recrystallization, column chromatography and the like.